ArticleThe New England journal of medicine2012
Somatic STAT3 mutations in large granular lymphocytic leukemia.
Article in The New England journal of medicine, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 437 papers, 1 of them a synthesis that pooled it.
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Who cites it
437 citing papers in PubMed, 1 synthesis or guideline pooled it, 756 citations in OpenAlex.
- Efficacy and influencing factors of immunosuppressive therapy for pure red cell aplasia: meta-analysis and systematic review.Annals of hematology · 2025Pooled it
- Trial
- Trial
- Stat3 mutations impact on overall survival in large granular lymphocyte leukemia: a single-center experience of 205 patients.Leukemia · 2020Trial
- Felty Syndrome-Associated Clonal Cytotoxic T-Cell Disease With Terminal Aggressive Progression: SharedEJHaem · 2026Article
- A practical approach to risk stratification of incidental T-cell clonality.Blood advances · 2026Review
- Clonal selection of somatic mutations shapes NK cell memory.bioRxiv : the preprint server for biology · 2026Article
- Targeting the JAK/STAT signalling axis in cancer: chemopreventive potential of natural compounds with emerging focus on retinoids.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Article
- T cell lymphomas: cancers of aberrant immune synapse signalling.Nature reviews. Immunology · 2026Review
- Anti-PAD4 antibodies link autoimmunity to PAD4 with CTL-associated rheumatoid arthritis.Annals of the rheumatic diseases · 2026Article
- Clinical Manifestations and Genetic Profile of Chinese Patients with NK-Cell Large Granular Lymphocytic Leukemia-A Single-Center Retrospective Analysis.International journal of molecular sciences · 2026Article
- Vitamin D Deficiency in Leukemia: Implications for Pathophysiology, Treatment, and Supportive Care.Nutrients · 2026Review
- Cancer-Associated STAT3 Mutations Maintain ES Cell Self-Renewal Through Phosphorylation-Independent Mechanisms.Genes to cells : devoted to molecular & cellular mechanisms · 2026Article
- [Efficacy and safety of a JAK1 inhibitor for relapsed/refractory large granular lymphocytic leukemia].Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi · 2026Article
- JAK-STAT signaling pathway in cancer: from molecular mechanisms to clinical intervention.Molecular cancer · 2026Review
- Mycobacterium intracellulare Infection in a Japanese Patient with Signal Transducer and Activator of Transcription-3 Gain-of-function Syndrome.Internal medicine (Tokyo, Japan) · 2026Article
- Targeted deep sequencing identifies mosaicism in patients with immune dysregulation.The Journal of allergy and clinical immunology · 2026Article
- Clinical relevance of mosaic variants detected by exome sequencing.The Journal of allergy and clinical immunology · 2026Article
- JAK Inhibitors in the Treatment of T-Cell Lymphomas: Current Evidence and Future Directions.Cancers · 2026Review
377 more citing papers are in PubMed but not listed here.
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Authors and funding
29 authors at 7 institutions in 2 countries.
Funding
Abstract
backgroundT-cell large granular lymphocytic leukemia is a rare lymphoproliferative disorder characterized by the expansion of clonal CD3+CD8+ cytotoxic T lymphocytes (CTLs) and often associated with autoimmune disorders and immune-mediated cytopenias.
methodsWe used next-generation exome sequencing to identify somatic mutations in CTLs from an index patient with large granular lymphocytic leukemia. Targeted resequencing was performed in a well-characterized cohort of 76 patients with this disorder, characterized by clonal T-cell-receptor rearrangements and increased numbers of large granular lymphocytes.
resultsMutations in the signal transducer and activator of transcription 3 gene (STAT3) were found in 31 of 77 patients (40%) with large granular lymphocytic leukemia. Among these 31 patients, recurrent mutational hot spots included Y640F in 13 (17%), D661V in 7 (9%), D661Y in 7 (9%), and N647I in 3 (4%). All mutations were located in exon 21, encoding the Src homology 2 (SH2) domain, which mediates the dimerization and activation of STAT protein. The amino acid changes resulted in a more hydrophobic protein surface and were associated with phosphorylation of STAT3 and its localization in the nucleus. In vitro functional studies showed that the Y640F and D661V mutations increased the transcriptional activity of STAT3. In the affected patients, downstream target genes of the STAT3 pathway (IFNGR2, BCL2L1, and JAK2) were up-regulated. Patients with STAT3 mutations presented more often with neutropenia and rheumatoid arthritis than did patients without these mutations.
conclusionsThe SH2 dimerization and activation domain of STAT3 is frequently mutated in patients with large granular lymphocytic leukemia; these findings suggest that aberrant STAT3 signaling underlies the pathogenesis of this disease. (Funded by the Academy of Finland and others.).
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